Genome-wide association studies have identified significant association between PLA2G1B gene polymorphisms and central adiposity in humans. This gene encodes the Group 1B phospholipase A2 protein (PLA2G1B) that hydrolyzes phospholipids to generate free fatty acids and lysophospholipids (lysoPL) in the digestive tract. Recent lipidomic analyses have also identified elevated lysoPL as a major obesity risk factor in humans, thus suggesting that PLA2G1B-mediated production of lysoPL may contribute to obesity and its related metabolic consequences. This project has documented previously that Pla2g1b inactivation in mice decreases intestinal lysoPL absorption, and as a consequence decreases hepatic fatty acid oxidation in protection against diet-induced obesity and glucose intolerance. This renewal application will delineate the mechanism by which intestinal lysoPL absorption suppresses hepatic fatty acid oxidation, and test the hypothesis that PLA2G1B-mediated lysoPL absorption and transport to the liver is a major contributing factor for diet-induced metabolic diseases including obesity, diabetes, and atherosclerosis. The second goal of this application is to delineate the molecular mechanism linking the common PLA2G1B polymorphism with decreased adiposity in humans. Aim 1 will test the hypothesis that lysoPL suppresses hepatic fatty acid oxidation and promote diet-induced obesity and glucose intolerance by inducing transient opening of mitochondrial permeability transition pores and/or activating JNK stress signaling to suppress PPAR activity. The direct role of hepatic lysoPL toward these metabolic disorders will be assessed by determining if converting lysoPL to phospholipids by increasing lysoPC acyltransferase specifically in liver will improve fatty acid oxidation and ameliorate diet-induced metabolic disorders in Pla2g1b+/+ mice similar to that in Pla2g1b-/- mice. Aim 2 is a proof of concept pre-clinical study to evaluate the efficacy of oral Pla2g1b inhibitor therapy in suppressing atherosclerosis in hypercholesterolemic Ldlr-null mice. The specific role of Pla2g1b will be ascertained in complementary studies comparing atherosclerosis development between Pla2g1b+/+Ldlr-/- and Pla2g1b-/- Ldlr-/- mice. Aim 3 will identify the mechanism by which the common PLA2G1B polymorphism (rs5637; allelic frequency ~20%) is associated with reduced obesity in humans, testing the hypothesis that the synonymous G-to-A mutation alters an exon splicing enhancer sequence within exon 3 of the PLA2G1B gene, resulting in alternative splicing and deletion of the exon 3 domain to yield an inactive enzyme. Taken together, these studies will not only contribute valuable information toward understanding the mechanism by which PLA2G1B-induced lysoPL promotes metabolic disorders, thereby accelerating the development of PLA2G1B inhibitors for disease intervention, but will also help identify subjects that may benefit the most from this novel therapeutic strategy.